2-benzyloxyimino cyclic amines

ABSTRACT

Cyclic amines having a benzyloxyimino substituent at the 2position are described herein. They possess anti-hypertensive, anti-protozoal, anti-fungal, and anti-algal activity. The compounds are prepared from the appropriate 2-alkoxy cyclic amine or 2-hydroxyimino cyclic amine.

llllieed States Patent [151 3,694,432 Hershenson 51 Sept. 26, 1972Z-BENZYLOXYIMINO CYCLIC AMINES Primary Examiner-Alton D. Rollins vAttorney-John M. Brown, John J. Kolano, Elliot N. [72] gg gggg m GmveSchubert, Lowell c. Bergstedt, Sybil Meloy, Walter c.

Ramm and Helmuth A. Wegner [73'] Assignee: G. D. Searle and Company,Chicago, r I l ll]. [57] ABSTRACT Filed; March 1971 Cyclic amines havinga benzyloxyimino substituent at [211 App] No 119 907 the 2-position aredescribed herein. They possess antihypertensive, anti-protozoa],anti-fungal, and antiv algal activity. The compounds are prepared fromthe [52] U.S. Cl. ....260/239 B, 260/239 BE, 260/293.62, appropriate2-alkoxy cyclic amine or 2-hydroxyimino 260/293.78, 260/296 M, 260/3265L, cyclic amine.

424/244, 424/267, 424/274 511 Im. Cl.....C07d 27/02, C07d 29/26, C07d41/04 5 QF'F'FfiN? D'PPYP Field of Search ..260/239 B, 239 BE, 326.5 L,

2-BENZYLOXYIMINO CYCLIC AMINES The present invention relates to a groupof compounds which are 2-benzyloxyimino derivatives of cyclic amines.MOre particularly, it relates to a group of compounds having thefollowing general formula L lN-o-oHr-z N wherein n is a whole numberbetween 1 and 3 inclusive; and Z is selected from the group consistingof phenyl, naphthyl, tolyl, xylyl, halophenyl, and dihalophenyl. Thehalogen in the halophenyl and dihalophenylradicals referred to aboveinclude fluorine, chlorine, bromine, and iodine.

The organic bases of this invention form pharmaceuticallyacceptablesalts with a variety of inorganic and strong organic acids. Such saltsare formed with acids such as sulfuric, phosphoric, hydrochloric,hydrobromic, hydriodic, sulfamic, citric, lactic, maleic,

malic, succinic, tartaric, cinnamic, acetic, benzoic, gluconic, ascorbicand related acids.

The compounds of the present invention are prepared by the reactionof abenzyl halide with a lhydroxyimino cyclic amine of the following formulawherein n is a whole number between 1 and 3 inclusive. The hydroxyiminocompound is converted to the corresponding salt by means of a strongbase such as sodiurn methoxide and this salt is then reacted with thebenzyl halide. The reaction is most conveniently carried out in analcoholic solution corresponding to that from which the strong base isderived.

Alternatively, the present compounds can be prepared by the reaction ofa O-benzylhydroxylamine with an imido ester of the following formulaCHall O -Alkyl with various known excipients and adjuvants in the formof dusts, solutions, suspensions, ointments, and sprays to providecompositions useful for disinfecting purposes.

Evidence of the anti-protozoa] utility of the present compounds isprovided by a standardized test for their capacity to inhibit the growthof Tetrahymena pyriformis which is carried out in the following manner.A

solution is prepared from 24 grams of proteose peptone, 16 grams ofsucrose and 1,000 ml. of distilled water. 0.5 Ml. of this solution isinoculated with 10 percent of a 4 to 7 day old culture of Tetrahymenapyrzformis and the resultant mixture is added to 0.5 ml. of a solutionor suspension containing 2,000 micrograms of test compound permilliliter of solution. The resultant mixture is incubated at roomtemperature for 48 hours and then examined microscopically for thepresence of motile protozoa. if any are observed, the compound isconsidered inactive at a concentrationof 1,000 micrograms permilliliter. If no motile protozoa are observed, 0.1 ml. of the solutionor suspension is transferred from the original vial to 0.9 ml. of asolution which is prepared from 12 grams of proteose peptone, 8 grams ofsucrose, and 1,000 ml. of distilled water and which has been inoculatedwith 5 percent of a 4 to 7 day old culture of Tetrahymena pyriformis andthe resultant mixture "is thoroughly mixed. 0.1 Ml. of this preparationis transferred similarly to a second vial of inoculated 'medium and,after mixing, 0.1 ml. of this new preparation is similarly transferredto a third vial. The resultant mixtures are incubated as before andexamined microscopically for the presence of motile protozoa. Theresulting solutions contain the test compounds at concentrations of 100,10, and l microgram per milliliter, respectively. Controls are providedby concurrent incubations identical with the foregoing except for theabsence of test compound. When 2-benzyloxyiminopyrrolidine, 2-(4-chlorobenzyloxyimino)pyrrolidine, and2(2-chlorobenzyloxy)-hexahydro-2l-lazepine were tested by the aboveprocedure, each inhibited the protozoa at a concentration of 1,000micrograms per milliliter or less.

The following examples are presented to further illustrate the presentinvention; they should not be construed as limiting it in spirit or inscope. In these examples, temperatures are indicated in degreescentigrade (C.) and quantities are indicated in parts by weight unlessparts by volume are specified. The relationship existing between partsby weight and parts by volume is the same as that existing between gramsand milliliters.

EXAMPLE 1 A solution of 2.0 parts of Z-methoxy-l-pyrroline, 3.5 parts ofO-benzylhydroxylamine hydrochloride and 2.4 parts of sodium bicarbonatein 20 parts of methanol and 15 parts of water is refluxed for 22 hours.The mixture is cooled and 25 parts of water is added and an oil forms.The mixture is extracted with 3 portions of chloroform and the combinedchloroform extracts are dried over anhydrous magnesium sulfate. Thesolvent is then removed under reduced pressure and the residual oil isdistilled to give 2-benzyloxyiminopyrrolidine boiling at about l23l 27C. at 0.6 mm. pressure.

The oil is dissolved in 35 parts of ether and parts by volume of anether solution saturated with hydrogen chloride gas is added. The whiteprecipitate which forms is separated by filtration and washed with etherto give 2-benzyloxyiminopyrrolidine hydrochloride melting at aboutl62-l65 C. The free base of this compound has the following formulaEXAMPLE 2 A solution of 2.0 parts of 2-pyrrolidone oxime in parts ofmethanol is cooled to 10 C. and there is added, with stirring, asolution of 1.1 part of sodium methoxide in 16 parts of methanol. Theresultant solution is stirred at l520 C. for minutes and then there isadded portionwise, with stirring, a solution of 2.9 parts of2-fiuorobenzyl chloride in 5 parts of methanol. The mixture is stirredat room temperature for 45 minutes and it is then heated at reflux for 3hours. After the mixture is allowed to stand at room temperature for 16hours, it is filtered and 100 parts of water is added to the filtrate.The mixture is then extracted with 2 portions of chloroform and thecombined chloroform extracts are washed with water and dried over sodiumsulfate. The solvent is removed under reduced pressure and the residueis distilled to give a liquid boiling at about l181 19 C. at 0.4 mm.pressure. This liquid is dissolved in parts of ether and 5 parts byvolume of a 25 percent solution of hydrogen chloride in 2-propanol isadded. The precipitate which forms is separated by filtration and washedwith ether and then recrystallized from acetonitrile. The productobtained in this way is 2- (2fluorobenzyloxyimino)-pyrrolidine meltingat about l73-l 75 C.

EXAMPLE 3 If the procedure of Example 2 is repeated using 2- pyrrolidoneoxime and 4-chlorobenzyl chloride, 2-(4-chloro-benzyloxyimino)pyrrolidine is first obtained as a liquid boilingat about l35l 37 C. at 0.25 mm. pressure. This material solidifies andis recrystallized from hexane to give a solid melting at about 6869.5 C.Reaction of this material with isopropanolic hydrogen chloride gives thecorresponding hydrochloride melting at about l70.517l.5 C.

Similarly, 2-pyrrolidone oxime is converted to the sodium salt andreacted with 4-methylbenzyl chloride to give 2-(4-methylbenzyloxyimino)pyrrolidine.

In a similar manner, 2-pyrrolidone oxime is converted to the sodium saltand reacted with 2,6- dichlorobenzyl chloride. In this case, it is notnecessary to distill the crude product because it solidifies whentriturated with a small amount of hexane. The solid is recrystallizedfrom hexane to give 2-(2,6- dichlorobenzyloxyimino)pyrrolidine meltingat about 8794 C. This solid is dissolved in ether and reacted withhydrogen chloride gas in 2-propanol. The solid which precipitates isseparated by filtration and recrystallized from acetonitrile to give2-(2,6-

dichlorobenzyloxyimino)pyrrolidine melting at about l82.5-l84 C.

EXAMPLE 4 A solution of 7.5 parts of 2-pyrrolidone oxime in parts ofmethanol is treated at room temperature with a solution of 4 parts ofsodium methoxide in 8 parts of methanol. The resulting solution isstirred at room temperature for 1 hour and then 17.7 parts of 1-chloromethylnaphthalene is added. The mixture is then refluxed for 4hours before it is cooled and filtered and the solvent is evaporatedfrom the filtrate under reduced pressure. The resulting orangesemi-solid residue is partitioned between parts of benzene and parts of5 percent aqueous hydrochloric acid. Three layers form and the thicklower layer is removed. The remaining two layers are separated and theaqueous layer is extracted a second time with benzene. The acidicaqueous layer is then made alkaline by the addition of 50 parts of 10percent aqueous sodium hydroxide solution and the resulting mixture isextracted with 3 portions of chloroform. The combined chloroformextracts are washed with water and dried over anhydrous sodium sulfate.The solvent is evaporated under reduced pressure and the residue isdistilled to give a yellow-orange oil boiling at about l76180 C. at 0.3mm. pressure. The oil is dissolved in parts of ether and hydrogenchloride in 2-propanol is added until no further precipitation takesplace. The solid is then separated by filtration and washed with ether;it is recrystallized from a mixture of ethanol and ether to give 2-(l-naphthylmethoxyimino )-pyrrolidine hydrochloride melting at aboutll5-l20 C., ISO-153C. The free base of this compound has the w g prEXAMPLE 5 A solution of 6.5 parts of hexahydro-2H-azepin-2- one oxime in80 parts of methanol is treated with a solution of 2.7 parts of sodiummethoxide in 20 parts of methanol and the resulting mixture is stirredat 25 C. for 1.5 hours. To this solution is added 16.1 parts of 2-chlorobenzyl chloride and the mixture is heated at reflux for 4 hours.It is then cooled and filtered and the solvent is evaporated from thefiltrate under reduced pressure. The residue is dissolved in 100 partsof 5 per cent hydrochloric acid and this is extracted with benzene. Theaqueous solution is made alkaline with 5 percent aqueous sodiumhydroxide solution and it is then extracted with 2 portions ofchloroform. The combined chloroform extracts are dried over sodiumsulfate and the solvent is evaporated under reduced pressure to leave aresidual oil. Distillation of the oil gives material boiling at aboutl50155 C. at 0.3 mm. pressure. The oil is dissolved in 45 parts of etherand a solution of hydrogen chloride in 2-propanol is added. Theprecipitate which forms is separated by filtration and washed with etherto give 2-(2-chlorobenzyl-oxyimino)hexahydro-2H-azepine hydrochloridemelting v to give at about l83-184 C. The free base of this compound hasthe following formula EXAMPLE 6 The procedure of Example 5 is repeatedusing 3.2 parts of hexahydro-ZH-azepin-Z-one oxime and 8 parts of3-chlorobenzyl chloride. This first gives 2-(3-chlorobenzyl-oxyimino)hexahydro-ZH-azepirie boiling at about 149-l52 C.at 0.3 mm. pressure. This is then converted to the hydrochloridesalt-which melts at about l62--l63 C. after recrystallization from a mixture of ethanol and ether.

In a similar manner, 6.4 parts of hexahydro-2l-I- azepin-Z-one oxime isreacted with 16.1 parts of 4- chlorobenzyl chloride. In this case, thecrude product solidifies on cooling so it is not distilled. The crudesolidified solid is triturated with hexane and the solid remaining isremoved by filtration and washed several times with hexane. The solventis then evaporated from the hexane filtrate and the resulting solid isdissolved in 70 parts of dry ether and hydrogen chloride in 2- propanolis added. The solid which precipitates is separated by filtration andrecrystallized from acetone2-(4-chlorobenzyloxyimino)hexahydro-Zl-lazepine hydrochloride melting atabout l68-l69 C;

Similarly, hexahydro-2H-azepin-2-one oxime reacts with2,6-dimethylbenzyl chloride to give 2-(2,6-dimethyl-benzyloxyimino)hexahydro-2H-azepine as the hydrochloride.

EXAMPLE 7 A solution of 6.4 parts of hexahydro-2H-azepin-2- one oxime in80 parts of methanol is treated with 2.7 parts of sodium methoxide in 20parts of methanol and the resulting mixture is stirred at roomtemperature for 90 minutes. Then, 19.6 parts of 2,6-dichlorobenzylchloride is added in one portion and the mixture is refluxed for 3hours. It is then cooled to room temperature and filtered and 150 partsof water is added to the filtrate. The filtrate is extracted with 3portions of chloroform and the combined chloroform extracts are washedwith water and dried over sodium sulfate. The

solvent is then evaporated under reduced pressure and the residualyellow oil is extracted by boiling with parts by volume of hexane. Themixture is filtered and cooled and the solid which precipitates isseparated by filtration and dissolved in anhydrous ether. The ethersolution is treated with hydrogen chloride in 2- propanol and thesupernatant liquid is decanted from the gummy hydrochloride precipitate.This is washed with several portions of ether and then recrystallizedfrom a mixture of ethanol and ether to give 2-(2,6-dichlorobenzyloxyimino)hexahydro-ZH-azepine hydrochloride melting atabout l 73.5- 1 74 C.

EXAMPLE 8 The procedure of Example 2 is repeated using 2- What isclaimed is:

l. A compound of theformula (cm). I

L lN-O-CHP Z wherein n is a whole number between 1 and 3 inclusive; andZ isselected from the group consisting of phenyl, naphthyl, tolyl,xylyl, halophenyl, and dihalophenyl.

2. A compound according to claim 1 which is 2-(1-naphthylmethoxyimino)pyrrolidine.

3. A compound according to claim 1 which has the formula 4. A compoundaccording to claim 1 which is 2-(2-chlorobenzyloxyimino)hexahydro-ZH-azepine.

5. A compound according to claim 1 which is 2-(2,6-dichlorobenzyloxyimino)hexahydro-ZH-asepine.

UNITED STATES PATENT oTTTTJT: CERTEFECATE 0F (MRREQTWNPacenttm.3,69fl,u32 Dated September 26, 1972 Invmuw Fred M. HershensonIt is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 1, line 67, "present compounds" should be The present compoundsColumn 3, line 39, "(2fluorobenzyloxyimino)" should be(2fluorobenzyloxyimino)- Column 3, line 40, "-175C." should be 'l75.5C.-g

and I l Column 6, line l8,-")piperidone" should be )piperidine Signedand sealed this 18th day of December 1973.-

(SE-AL) Attest;

EDWARD M; FLETCHER, JRo RENE Do TEGTMEYER- Attesting Officer ActingCommissioner of Patents

2. A compound according to claim 1 which is2-(1-naphthylmethoxyimino)pyrrolidine.
 3. A compound according to claim1 which has the formula
 4. A compound according to claim 1 which is2-(2-chlorobenzyloxyimino)hexahydro-2H-azepine.
 5. A compound accordingto claim 1 which is 2-(2,6-dichlorobenzyloxyimino)hexahydro-2H-asepine.